LMO4, a member of the nuclear LMO family of proteins, has been shown in multiple developmental contexts to play a critical role in the processes of differentiation, migration, and proliferation by modulating multimeric transcription complexes without directly binding DNA. Given that tumors often aberrantly express genes that are required for normal development and tissue homeostasis, it is not surprising that LMO4 has been implicated in solid tumor pathogenesis, in which it is required and sufficient for tumor cell proliferation, migration, and invasion. Additionally, high nuclear LMO4 expression in tumor cells correlates with increased metastasis in patients with breast cancer, rhabdomyosarcoma, or oral squamous cell carcinoma. Intriguingly, LMO4 is also detected in pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignancy that is the fourth leading cause of cancer-related mortality, yet this finding remains unexplored. Preliminary data indicate that a reduced level of endogenous LMO4 in human PDAC lines results in impairment of cells to close a scratch wound in vitro, suggestive of reduced proliferation and/or compromised migration. Additionally, knockdown of LMO4 in a human PDAC cell line results in reduced expression of PLAU, which encodes a serine protease implicated in PDAC disease progression. The central hypothesis of this proposal is that LMO4 regulates gene programs that affect proliferation, migration, and invasion, thereby augmenting disease progression. Based on this hypothesis, two specific aims will be pursued.
Specific Aim 1 : To determine the phenotypes affected by and direct transcriptional targets of LMO4 in PDAC.
Specific Aim 2 : To identify protein interactors of LMO4 in modulating malignant phenotypes in PDAC. To complete these studies, in vitro and in vivo methods of biochemistry, genetics, animal modeling, immunohistochemistry, and bioinformatics will be used. The objective of this proposal is to elucidate novel pathogenic mechanisms of this highly aggressive malignancy, potentially yielding novel therapeutic targets, and to glean novel insight into how a transcriptional coregulator can orchestrate gene programs to coordinate specific cellular phenotypes, which may have far-reaching consequences in other developmental and oncogenic contexts.
Pancreatic cancer is one of the leading causes of cancer-related death in the United States and is almost universally fatal due to late stage of diagnosis and lack of effective therapies. Although we have recently gained an appreciation for several mechanisms by which pancreatic cancer spreads throughout the body, a much deeper insight is still needed to be able to treat this cancer effectively. Therefore, we are proposing to study how a single protein can coordinate the processes of tumor spreading and progression, potentially yielding multiple novel therapeutic targets.
|Ferreira, Mark J; McKenna, Lindsay B; Zhang, Jia et al. (2015) Spontaneous Pancreatitis Caused by Tissue-Specific Gene Ablation of Hhex in Mice. Cell Mol Gastroenterol Hepatol 1:550-569|